Abstract
Background
Aplastic anemia (AA) is a bone marrow failure syndrome. Whether the combination of TPO-RAs and IST is superior to IST alone is an ongoing debate. This meta-analysis compares the efficacy of EPAG+IST versus IST alone, and assesses the initiation timing and treatment duration of eltrombopag (EPAG) across different age groups of AA patients.
Methods
The literature was retrieved from Chinese and English databases up to October 1, 2025. The analysis was conducted using RevMan 5.4 software, employing a fixed-effects model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the outcomes. The I² statistic was used to assess heterogeneity among included studies.
Results
21 studies involving 2,239 patients were included. The overall response rate in the EPAG+IST group was higher at 3 months (OR = 2.13, 95% CI 1.65 – 2.74, P < 0.00001) and 6 months (OR = 2.13, 95% CI 1.73 – 2.61, P < 0.00001). There was no significant difference between the two groups at 12 months (OR = 1.14, 95% CI 0.86 – 1.51, P = 0.36, I² = 35%).
Conclusion
The addition of EPAG to IST may improve early hematological responses at 3 and 6 months in patients with AA, with no significant difference at 12 months. Concurrent initiation (within 7 days) was associated with earlier responses in adults.
Systematic review registration
https://www.crd.york.ac.uk/prospero/, identifier CRD42024604778
Keywords: aplastic anemia (AA), bone marrow failure (BMF), eltrombopag (EPAG), immunosuppressive therapy (IST), thrombopoietin receptor agonists (TPO-RA)
Highlights
In patients with AA, the addition of EPAG to IST improves hematological responses within 3 to 6 months compared with IST alone, with no significant difference at 12 months.
In adults, concurrent initiation of EPAG with IST (within 7 days) was associated with improved responses at 3 months, while delayed initiation (>7 days) showed benefit by 6 months.
In children, no significant added benefit from EPAG was observed at 3 months, with responses emerging by 6 months.
1. Introduction
Aplastic anemia (AA), a bone marrow failure (BMF) syndrome, is characterized by marrow hypoplasia and peripheral blood cytopenia (1). The pathophysiology of BMF can arise from chemical or physical damage, a compromised immune system (primarily due to T cells), or constitutional genetic defects affecting immune regulation (2). The incidence of AA ranges from 0.6 to 7 cases per million people per year, with a higher rate observed in adolescents and older adults (3). Frontline treatment of AA depends on disease severity, donor availability, and patient age, primarily involving immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). Standard IST, including anti-thymocyte globulin (ATG) and cyclosporine A (CsA), yields a hematologic response rate and transfusion independence of 60 to 70% (4, 5). Nonetheless, about one-third of patients relapse, and 10 to 15% may develop cytogenetic abnormalities in the long term (5).
Eltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is effective in patients with AA refractory to immunosuppression (6, 7). Recent studies indicate that adding EPAG to IST is associated with significantly higher rates of hematologic response in patients with severe AA compared to standard IST (6, 8). However, response rates with EPAG combined with IST vary between adults and children (8, 9), and also depend on different EPAG maintenance durations (10). In clinical practice, there are no conclusive guidelines regarding the optimal timing for initiating and discontinuing EPAG for different populations. Therefore, we conducted this systematic review and meta-analysis to compare the efficacy of EPAG + IST with that of standard IST in patients with AA and to assess the optimal initiation and maintenance timing of EPAG in both adults and children.
2. Methods
The recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (11) were used to formulate the systematic review and meta-analysis eligibility criteria.
2.1. Eligibility criteria
Studies were eligible if they met the following criteria (PICOS framework): Population (P): patients diagnosed with AA of any age and severity; Intervention (I): EPAG combined with immunosuppressive therapy (EPAG+IST); Comparator (C): IST alone, including ATG-based regimens or CsA monotherapy; Outcomes (O): overall response and/or complete response at 3, 6, or 12 months; Study design (S): randomized controlled trials, prospective cohort studies, or retrospective cohort studies with a comparator arm. Case reports, single-arm studies without a comparator, conference abstracts, and review articles were excluded.
2.2. Search strategy
Eligible studies published before October 1, 2025, were retrieved by two independent authors (S. Tan and MY. Shang) from PubMed, EMBASE, Web of Science, the Cochrane Library, LILACS, CNKI, WANFANG, VIP, and the Chinese Biomedical Literature Database (CBM). The search terms used to retrieve relevant studies included “Aplastic Anemia”, “Eltrombopag” and “immunosuppressive therapy”. The detailed search strategy for each database is provided in Supplementary Table 1. Additional studies were identified from the bibliographies of screened articles as appropriate.
2.3. Outcomes and study selection
The primary outcomes were overall response (defined as either complete or partial response) and complete response at 3, 6, and 12 months. Complete response was defined according to each included study’s criteria, which generally required an absolute neutrophil count (ANC) ≥ 1.0 × 10 (9)/L, hemoglobin (Hb) ≥ 100 g/L, and a platelet count ≥ 100 × 10 (9)/L. The secondary outcome was partial response (as defined in each included study) at the same time points. Two authors (YX. Guo and L. Su) independently screened the titles and abstracts of all studies and subsequently examined the full texts of eligible studies. In cases of disagreement during the study selection process, consensus was reached through group discussion with a third author (HY. Wang).
2.4. Data extraction
Two authors (Q. Ma and WH. Hui) independently collated the baseline characteristics of each included study using a standardized Excel table. The baseline characteristics were as follows: (1) study data, including the first author, publication year, and study design; (2) patient data, encompassing the number of patients, age categories, and gender distribution; (3) grouping information, detailing the initiation time of EPAG and IST programs; and (4) primary and secondary outcomes.
2.5. Quality assessment and bias risk assessment
Two authors (J. Ni and ZH. Cai) independently evaluated the quality of observational studies using the Newcastle-Ottawa Scale (NOS). The NOS evaluates three domains—selection, comparability, and outcome assessment—with a maximum total score of 9 stars. Studies scoring ≥ 6 were considered high quality.
For randomized controlled trials (RCTs), the Cochrane Collaboration tool was employed. Assessments were categorized as “low risk of bias,” “unclear risk of bias,” or “high risk of bias” based on seven criteria: Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Any disagreements in this process were resolved through discussion or adjudication by a third author (HZ. He).
2.6. Statistical analysis
All statistical tests were conducted using RevMan 5.4 software. A fixed-effects model was used for the primary analyses to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for both primary and secondary outcomes. Statistical heterogeneity was assessed using the I² statistic and Cochran’s Q test. Subgroup analyses were performed based on the initiation time of EPAG (0–7 days vs. > 7 days), age (< 18 years vs. ≥ 18 years), and region (Asia vs. North America), with between-subgroup differences assessed by the chi-square test for interaction. Studies that included both pediatric and adult patients, EPAG initiation timing varied within the cohort, or that originated outside the predefined regional categories (Asia and North America) were excluded from the corresponding subgroup analyses. To assess the robustness of our findings, we conducted sensitivity analyses using the random-effects model (DerSimonian-Laird method) for all primary outcomes, and additional fixed-effects sensitivity analyses for the 6-month outcomes by (1) study design, (2) exclusion of studies with non-standard IST control arms, and (3) disease severity. For safety outcomes, quantitative pooling was performed when comparable two-arm data were available in at least three included studies.
3. Results
3.1. Outcomes of the search process
The initial search yielded a total of 2,609 records among all databases, from which 596 duplicates were detected and removed. After reviewing the titles and abstracts of the remaining 2,013 studies according to the exclusion criteria, 1,949 studies were excluded. We then examined the full texts of the remaining 64 articles, resulting in 21 studies that met the inclusion criteria and were ultimately included in our meta-analysis (Figure 1).
Figure 1.
A flow diagram depicting the search process used in this study.
3.2. Study characteristics and quality evaluation
The characteristics of the included studies are summarized in Table 1. In total, 2,239 patients were included in our meta-analysis, with 1,059 treated with EPAG + IST and 1,180 treated with IST alone. Of the 21 included studies, 7 were prospective (4 were RCTs) and 14 were retrospective. The quality assessments of the 17 cohort studies are shown in Table 2: 6 studies had a NOS score of 9, 5 studies had a score of 8, 4 studies had a score of 7, and 3 studies had a score of 6, all meeting the study criteria. The Cochrane risk of bias assessment for the 4 RCTs indicated low risk of bias and high quality, as presented in Supplemental Supplementary Figure 1.
Table 1.
Characteristics of included studies in the meta-analysis.
| Author | Year | Total no. | Study design | Disease severity | Age types of patients/years old | EPAG+IST | IST | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patients(n) | Gender (female/male) ,n | EPAG initiation time | Intervention | Patients(n) | Gender (female/male), n | Intervention | ||||||
| Assi (9) | 2018 | 38 | Prospective study | Mixed | ≥ 18 | 21 | 10/11 | 0-7 days | EPAG+hATG+CsA | 17 | 8/9 | hATG+CsA |
| Cai (32) | 2021 | 86 | Retrospective study | Mixed | Mixed | 42 | 22/20 | 0-7 days | EPAG+CsA | 44 | 23/21 | CsA |
| Chai (33) | 2021 | 35 | Retrospective study | SAA | ≥ 18 | 24 | 9/15 | 0-7 days | EPAG+rATG+CsA | 11 | 6/5 | rATG+CsA |
| De Latour (8) | 2022 | 197 | RCT | SAA/VSAA | Mixed | 96 | 49/52 | >7 days | EPAG+hATG+CsA | 101 | 49/52 | hATG+CsA |
| Fang (12) | 2021 | 57 | Retrospective study | SAA/VSAA | <18 | 18 | 8/10 | >7 days | EPAG+pATG+CsA | 39 | 18/21 | pATG+CsA |
| Fang (13) | 2023 | 90 | RCT | Mixed | Mixed | 45 | 22/23 | 0-7 days | EPAG+rATG+CsA | 45 | 22/23 | rATG+CsA |
| Goronkova (19) | 2023 | 98 | RCT | SAA/VSAA | <18 | 49 | 14/35 | 0-7 days | EPAG+hATG+CsA | 49 | 19/30 | hATG+CsA |
| Groarke (14) | 2021 | 127 | Prospective study | SAA | <18 | 40 | 17/23 | 0-7 days | EPAG+hATG+CsA | 87 | 36/51 | hATG+CsA |
| Hu (15) | 2022 | 111 | Retrospective study | SAA/VSAA | Mixed | 37 | 13/24 | >7 days | EPAG+r/pATG+CsA | 74 | 40/34 | r/pATG+CsA |
| Jie (16) | 2021 | 42 | Retrospective study | Mixed | <18 | 14 | NA | Variable timing | EPAG+rATG+CsA | 28 | NA | rATG+CsA |
| Jin (10) | 2022 | 121 | Retrospective study | SAA/VSAA | ≥ 18 | 54 | 26/28 | 0-7 days | EPAG+rATG+CsA | 67 | 30/37 | rATG+CsA |
| Lesmana (20) | 2021 | 25 | Retrospective study | SAA | <18 | 9 | 2/7 | 0-7 days | EPAG+hATG+CsA | 16 | 12/4 | hATG+CsA |
| Liang (34) | 2023 | 89 | Retrospective study | Mixed | ≥ 18 | 42 | 23/19 | 0-7 days | EPAG+CsA | 47 | 24/23 | CsA |
| Lin (17) | 2023 | 76 | Retrospective study | NSAA | ≥ 18 | 45 | 24/21 | 0-7 days | EPAG+CsA | 31 | 16/15 | CsA |
| Martynova (35) | 2021 | 21 | Retrospective study | Mixed | ≥ 18 | 12 | 8/4 | 0-7 days | EPAG+hATG+Tacrolimus | 9 | 6/3 | hATG+Tacrolimus |
| Patel (28) | 2022 | 280 | Prospective study | SAA/VSAA | Mixed | 178 | NA | Variable timing | EPAG+hATG+CsA | 102 | NA | hATG+CsA |
| Shinn (27) | 2023 | 82 | Retrospective study | SAA/VSAA | ≥ 18 | 48 | 23/25 | 0-7 days | EPAG+hATG+CsA | 34 | 16/18 | hATG+CsA |
| Yang (18) | 2021 | 125 | RCT | Mixed | ≥ 18 | 63 | 25/38 | 0-7 days | EPAG+CsA | 62 | 27/35 | CsA |
| Zaimoku (25) | 2021 | 416 | Retrospective study | SAA | ≥ 18 | 176 | 89/87 | Variable timing | EPAG+hATG+CsA | 240 | 99/141 | hATG+CsA |
| Zhang (36) | 2022 | 63 | Retrospective study | SAA | <18 | 31 | 15/16 | 0-7 days | EPAG+rATG+CsA | 32 | 16/16 | rATG+CsA |
| Zhao (37) | 2023 | 60 | Retrospective study | SAA/VSAA | <18 | 15 | 5/10 | 0-7 days | EPAG+r/pATG+CsA | 45 | 19/26 | r/pATG+CsA |
EPAG, Eltrombopag, IST: Immunosuppressive therapy; RCT, Randomized controlled trial; NA, no report; SAA, severe aplastic anemia; VSAA, very severe aplastic anemia; NSAA, non-severe aplastic anemia; hATG, horse antithymocyte globulin; rATG, rabbit antithymocyte globulin; pATG, pig antithymocyte globulin; CsA, Cyclosporin A.
Table 2.
Quality assessment of observational studies included in this meta-analysis.
| Selection | Comparability | Outcome/Exposure | Scores | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Representativ-eness of the exposed cohort | Selection of the non-exposed cohort | Determination of exposure | Ascertainment of no outcome before the study | Matching the most important factors | Control of confounding factors | Evaluation of outcome | Adequacy of follow up | Adequacy of follow up | ||
| Zhao (37) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
| Patel (35) | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 8 |
| Jin (10) | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 8 |
| Martynova (35) | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 1 | 1 | 7 |
| Fang (13) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
| Lesmana (20) | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 6 |
| Lin (17) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
| Zhang (36) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
| Zaimoku (25) | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 6 |
| Jie (16) | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 6 |
| Groarke (14) | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 7 |
| Fang (13) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
| Assi (9) | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 8 |
| Hu (15) | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 8 |
| Chai (33) | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 1 | 1 | 7 |
| Liang (34) | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 8 |
| Cai (32) | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 7 |
| Shinn (27) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the observational studies. Scores ranged from 0 to 9: scores of 1 or less were considered low quality (high risk of bias), scores of 2–5 were medium quality (unclear), and scores of 6–9 were high-quality literature (low risk of bias).
3.3. Outcomes of this meta−analysis
3.3.1. Overall response
The overall response after 3 months was evaluated in 14 studies, encompassing 1,159 patients with AA (Figure 2A). The results indicated that the overall response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.13, 95% CI 1.65–2.74, P < 0.00001), with low heterogeneity among these studies (P = 0.10, I² = 34%). At 6 months, 18 studies including 1,990 patients with AA were evaluated (Figure 2B), showing a similar trend: the overall response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.13, 95% CI 1.73–2.61, P < 0.00001), again with low heterogeneity (P = 0.24, I² = 18%). At 12 months, 10 studies with 953 patients were assessed (Figure 2C), revealing no significant difference between the EPAG + IST and IST alone groups according to the pooled results (OR=1.14, 95% CI 0.86–1.51, P = 0.36, I² = 35%).
Figure 2.
Overall response at 3, 6, and 12 months. (A) Overall response at 3 months. (B) Overall response at 6 months. (C) Overall response at 12 months. EPAG, Eltrombopag; IST, Immunosuppressive therapy; CI, Confidence interval.
3.3.2. Complete response
The complete response at 3 months was evaluated in 13 studies involving 1,124 patients with AA (Figure 3A). Our analysis suggested that the complete response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.31, 95% CI 1.63–3.28, P < 0.00001), with no heterogeneity (P = 0.94, I² = 0%). At 6 months, 17 studies including 1,955 patients were assessed (Figure 3B), indicating a higher complete response rate in the EPAG combined with IST group (OR=2.37, 95% CI 1.92–2.94, P < 0.00001), with some heterogeneity present (P = 0.06, I² = 37%). At 12 months, 10 studies with 953 patients were analyzed (Figure 3C), finding no significant difference between the EPAG + IST and IST alone groups (OR=1.32, 95% CI 0.99–1.75, P = 0.06, I² = 16%).
Figure 3.
Complete response at 3, 6, and 12 months. (A) Complete response at 3 months. (B) Complete response at 6 months. (C) Complete response at 12 months. EPAG, Eltrombopag; IST, Immunosuppressive therapy; CI, Confidence interval.
3.3.3. Subgroup analysis
Subgroup analysis based on EPAG initiation time was performed using overall response and complete response after 3 and 6 months as indices (Figure 4). The start of IST treatment was designated as day 0, with subgroup analyses separating EPAG initiation at day 7 after IST treatment as the cut-off. The results for the 0-7 days EPAG initiation subgroup indicated that IST combined with EPAG improved both overall and complete responses at 3 and 6 months for AA patients. Conversely, the >7 days EPAG initiation subgroup showed improvements in overall and complete responses only at 6 months. Overall, the P-values for interactions were greater than 0.05, indicating that the overall and complete responses were not significantly influenced by the timing of EPAG initiation in AA patients.
Figure 4.
Subgroup analysis of EPAG initiation time at 3 and 6 months. (A) Overall response at 3 months. (B) Complete response at 3 months. (C) Overall response at 6 months. (D) Complete response at 6 months. EPAG, Eltrombopag; IST, Immunosuppressive therapy; CI, Confidence interval.
3.3.4. Subgroup analysis of different ages
Subgroup analysis was performed using overall response and complete response at 3, 6, and 12 months as indices, categorized by age (Figure 5). The results for the subgroup of patients aged <18 years (children) indicated that IST combined with EPAG improved overall and complete response at 6 months. However, there was no effect at 3 and 12 months. For the subgroup of patients aged ≥18 years (adults), IST combined with EPAG improved overall response and complete response at 3 and 6 months. Additionally, it affected overall response at 12 months but did not influence complete response at that time. Overall, the P-value for the interaction of overall response at 3 months was less than 0.05, indicating that the age of AA patients had a significant effect on this response.
Figure 5.
Subgroup analysis of different ages at 3, 6, and 12 months. (A) Overall response at 3 months. (B) Complete response at 3 months. (C) Overall response at 6 months. (D) Complete response at 6 months. (E) Overall response at 12 months. (F) Complete response at 12 months. EPAG, Eltrombopag; IST, Immunosuppressive therapy; CI, Confidence interval.
3.3.5. Subgroup analysis of different regions
Using overall response and complete response at 3, 6, and 12 months as indices, subgroup analysis was performed by region (Figure 6). The analysis for the Asian region revealed that IST combined with EPAG improved overall response and complete response at 3 and 6 months, but had no effect at 12 months. In contrast, the North America (NA) region analysis indicated that IST combined with EPAG had no effect except on complete response after 6 months.
Figure 6.
Subgroup analysis of different regions at 3, 6, and 12 months. (A) Overall response at 3 months. (B) Complete response at 3 months. (C) Overall response at 6 months. (D) Complete response at 6 months. (E) Overall response at 12 months. (F) Complete response at 12 months. EPAG, Eltrombopag; IST, Immunosuppressive therapy; CI, Confidence interval; NA, North America.
3.3.6. Sensitivity analyses
To assess the robustness of our primary findings, we performed multiple sensitivity analyses focused on the 6-month outcomes, which represent the most clinically relevant time point with the largest pooled sample size.
First, random-effects analyses for all primary outcomes yielded pooled estimates highly consistent with the fixed-effects analyses, preserving both direction and statistical significance (Supplementary Figures 2, S3). Second, stratification by study design (3 RCTs versus 15 observational studies) showed consistent effects of EPAG+IST in both subgroups for both overall and complete responses, with no significant between-subgroup differences (test for subgroup differences: P = 0.63 and P = 0.26, respectively; Supplementary Figure 4). Yang 2021 did not report 6-month outcomes and was excluded from this analysis. Third, after excluding the two studies (Liang 2023 and Lin 2023) with CsA monotherapy control arms that reported 6-month data, the pooled estimates remained essentially unchanged (6-month ORR: OR = 2.10, 95% CI 1.69–2.60; 6-month CRR: OR = 2.66, 95% CI 2.12–3.34; Supplementary Figure 5), indicating that the observed benefit was not driven by indirectness bias from non-standard control regimens. Fourth, stratification by disease severity (12 SAA/VSAA studies versus 6 mixed/NSAA studies) showed consistent effects on overall response (test for subgroup differences: P = 0.22), but the complete response benefit was more pronounced in the SAA/VSAA subgroup (OR = 2.74) than in the mixed/NSAA subgroup (OR = 1.48; test for subgroup differences: P = 0.02; Supplementary Figure 6), suggesting that the CRR benefit of EPAG + IST may be more clearly demonstrated in more severe disease.
3.4. Publication bias
Stata 15 was used to evaluate publication bias in overall response and complete response at the 3, 6, and 12 months intervals. Begg’s and Egger’s tests were conducted, revealing no significant publication bias in this study (3 months ORR: Begg’s test P = 0.511, Egger’s test P = 0.669; 3 months CRR: Begg’s test P = 0.502, Egger’s test P = 0.697; 6 months ORR: Begg’s test P = 0.596, Egger’s test P = 0.479; 6 months CRR: Begg’s test P = 0.837, Egger’s test P = 0.879; 12 months ORR: Begg’s test P = 0.592, Egger’s test P = 0.797; 12 months CRR: Begg’s test P = 1.000, Egger’s test P = 0.854).
3.5. Adverse events
The most common adverse event related to EPAG is liver dysfunction, primarily characterized by increased bilirubin, aspartate aminotransferase, and alanine transaminase levels (8, 10, 12–18). Liver dysfunction led to treatment interruptions (7, 19) or dose reductions (20) in some study patients. Generally, liver function abnormalities in most AA patients were temporary and reversible; however, 10 out of 49 (20%) pediatric patients in Goronkova et al.’s study (19) experienced grade 3 to 4 liver function abnormalities that persisted for more than 21 days after drug discontinuation. Among the four studies that reported comparable two-arm data on any-grade hepatic dysfunction (de Latour 2022, Goronkova 2023, Jin 2022, and Lesmana 2021; 255 patients in the EPAG + IST group and 285 in the IST alone group), the pooled analysis showed no significant increase in hepatic dysfunction with the addition of EPAG (OR = 0.71, 95% CI 0.48–1.03, P = 0.07, I² = 8%; Supplementary Figure 7). In Lesmana et al.’s study, renal insufficiency was more prevalent among patients receiving EPAG. Additionally, gastrointestinal adverse reactions, primarily abdominal distension and mild diarrhea, were noted in Lin et al.’s study (17). None of these adverse events resulted in dose reduction or discontinuation of EPAG. Other reported adverse events included febrile neutropenia, infection, hypertension, skin hyperpigmentation, rash, myalgia, joint pain, and cardiac disorders. Quantitative pooling of other safety outcomes was not feasible due to inconsistent reporting or insufficient two-arm data across the included studies.
4. Discussion
Many studies have confirmed the efficacy of EPAG + IST versus IST alone for treating AA; however, a unanimous conclusion is still lacking. De Latour et al.’s multicenter trial (8) showed that complete response at 3 months was 10% in the IST combined with EPAG group and 22% in the IST group (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). There was no significant difference in overall response or complete response at 6 months. Conversely, Jin et al.’s study (10) demonstrated that the overall response rates (ORR) at 3, 6, and 12 months were higher in the IST combined with EPAG group (P = 0.002, 0.028, 0.006, 0.031), while the complete response rates (CRR) were similar between the two groups. Our meta-analysis indicated that overall response and complete response at 3 and 6 months improved in the IST combined with EPAG group compared to the IST group, with no significant differences at 12 months. Importantly, the robustness of our primary findings is supported by the consistency between fixed-effects and random-effects analyses (Supplementary Figures 2, S3). This suggests that adding EPAG can increase the rate, rapidity, and strength of hematologic responses in AA patients, with a desirable therapeutic effect sustained during 6 months of treatment.
Regarding clinical treatment, it remains to be determined when EPAG should be initiated after basic IST therapy for optimal results. The phase 2 NIH trial (6) suggested that the best outcomes were achieved when EPAG was introduced on day 0. To prevent possible cumulative toxicity from concurrent ATG administration, EPAG was initiated on day 14 in de Latour et al.’s trial (12), which found no detrimental effect on early hematologic response. Our subgroup analysis based on EPAG initiation time showed that concurrent therapy (adding EPAG within 7 days of IST treatment) significantly improved overall and complete responses at both 3 and 6 months, while delayed initiation (>7 days) showed significant improvements only at 6 months. Given that survival and long-term outcomes for AA patients correlate with the quality of hematologic response at 3 months and the presence of early recovery after ATG administration (21), our analysis suggests that concurrent therapy may be associated with a more favorable long-term prognosis for AA patients.
We also conducted a subgroup analysis based on age to assess whether age affected the efficacy of EPAG. Results indicated that EPAG + IST was more effective than IST alone in adults; however, in pediatric subgroup, the addition of EPAG did not demonstrate significant efficacy overall. Age is known to be a prognostic factor in AA patients treated with IST, particularly with antithymocyte globulin combined with cyclosporine being effective in children (21–24). We speculate that this discrepancy may be due to pediatric patients responding better to IST treatment than adults, resulting in a less significant effect of EPAG in the younger subgroup. Additionally, adult patients with AA may have a higher ANC than pediatric patients, and some studies suggest that EPAG is more effective in AA patients with higher ANC (25, 26). Although current guidelines do not include EPAG combined with standard IST therapy as a first-line treatment option for pediatric SAA, it has been demonstrated that EPAG not only increases ANC and CR rates in pediatric patients, but also that the early addition of EPAG can help rapidly identify nonresponders who are in urgent need of HSCT. The varying efficacy of EPAG among different age groups warrants further investigation in prospective stratified studies.
Subgroup analysis by region revealed that in the Asian subgroup, the addition of EPAG to IST significantly improved ORR and CRR at 3 and 6 months. In contrast, the North America (NA) subgroup showed no effect on overall response, except for complete response at 6 months. This discrepancy may stem from different indications for EPAG in various regions and patient age demographics. Currently, EPAG is approved only in specific countries to treat AA, with most patients in the NA subgroup having severe AA (SAA) or very severe AA (VSAA) (25, 27, 28). Additionally, two NA subgroup articles (14, 28) included pediatric patients, and the limited number of studies may have influenced the results of this analysis.
Sensitivity analyses further supported the robustness of our primary findings. The consistency of effects between RCT and observational study subgroups (Supplementary Figure 4) validated the pooling of studies with different designs, and the exclusion of studies with non-standard IST regimens (CsA monotherapy) yielded pooled estimates consistent with the primary analyses (Supplementary Figure 5), indicating that the observed benefit of EPAG+IST is not attributable to indirectness bias from heterogeneous control arms.
Sensitivity analysis by disease severity showed that while the effect on 6-month overall response was consistent across SAA/VSAA studies and mixed/NSAA studies, the complete response benefit was more pronounced in studies restricted to SAA/VSAA patients (Supplementary Figure 6). This pattern may reflect the greater residual hematopoietic capacity and favorable IST response of NSAA patients, leaving less room for additional benefit from EPAG, and may also be influenced by the higher proportion of non-standard control regimens within the mixed/NSAA subgroup.
Our quantitative analysis of any-grade hepatic dysfunction across four studies with comparable two-arm data showed no significant increase in liver function abnormalities with the addition of EPAG, supporting the overall hepatic safety of EPAG when combined with IST, although careful monitoring of transaminase and bilirubin levels remains essential. Beyond liver function abnormalities, the risk of clonal evolution from EPAG treatment cannot be overlooked. Current studies suggest that alterations in the immune bone marrow environment may contribute to the clonal evolution of AA patients (29), though the addition of EPAG has not significantly increased the risk of high-risk clonal evolution events (6, 30). Groarke et al. (30) evaluated predictors of clonal evolution in AA patients post-IST treatment, finding that pretreatment age > 48 years and ANC > 0.87 × 10 (9)/L were strong predictors of high-risk evolution. Moreover, RUNX1, splicing factor, and ASXL1 somatic mutations detected 6 months after IST treatment could predict high-risk evolution. In future IST or EPAG treatments, it is crucial to consider the characteristics of clonal evolution in AA patients and extend follow-up for targeted monitoring.
The strategy for tapering and discontinuation of EPAG also merits explicit consideration. First, the absence of incremental benefit beyond 12 months in our analysis suggests that prolonged exposure beyond one year is unlikely to yield further hematological gains once a sustained response has been achieved. Second, this is consistent with reports from the NIH cohorts, in which EPAG was successfully tapered and discontinued in patients with robust trilineage recovery (7), and in which relapses tended to cluster around cyclosporine withdrawal rather than EPAG cessation (28) — arguing against EPAG dependence as a major driver of relapse in deep responders. Third, theoretical risks associated with prolonged TPO-RA exposure — including persistent liver dysfunction (8, 10, 12–14), iron depletion as recently reported by Young et al. (31), and the earlier onset of clonal evolution (30) — further support minimizing unnecessary drug exposure. Collectively, these observations support a response-adapted approach in principle: continuing EPAG until a robust hematological response is consolidated, followed by gradual tapering and eventual discontinuation under structured monitoring for relapse and late clonal events.
Our meta-analysis has some limitations. First, among the 21 studies included, there were 17 cohort studies and 4 RCTs; therefore, the mixed results from different study types may affect the conclusions. Second, certain baseline characteristics, such as disease severity, were not consistently reported across included studies, potentially leading to bias. Our sensitivity analysis by severity suggested a more pronounced CRR benefit in SAA/VSAA studies than in mixed/NSAA studies, which should be interpreted cautiously given the relatively small mixed/NSAA subgroup. Third, definitions of complete response and partial response varied by region due to ethnic heterogeneity, which may also introduce potential bias. For example, the definition of complete response in Zhao et al.’s Asian study was an ANC ≥1.5×10 (9)/L, while in De Latour et al.’s European study, it was an ANC ≥1×10 (9)/L. Fourth, the included studies were heterogeneous with respect to EPAG maintenance and tapering protocols, which precluded a formal quantitative comparison of different tapering strategies. The absence of head-to-head data comparing fixed-duration with response-adapted regimens represents an important gap that should be addressed by future prospective trials.
5. Conclusion
Our results suggested that the combination of EPAG and IST may improve hematological responses in patients with AA compared to those treated with IST alone. The concurrent therapy of EPAG and IST and maintaining EPAG therapy for 3 to 6 months were associated with significant improvements in hematological responses. In the adult group, the hematologic responses of concurrent therapy and prolonged maintenance (≥ 3 months) were observed earlier, while in the pediatric group, responses tended to emerge later (EPAG response time ≥ 6 months). When EPAG was maintained for more than 12 months, no significant difference in outcomes was observed between the two age groups. The main adverse event associated with EPAG was liver dysfunction, indicating the importance of monitoring indicators such as transaminase and bilirubin levels.
Funding Statement
The author(s) declared that financial support was received for this work and/or its publication. The study was supported by grants from the National Natural Science Foundation of China (NSFC) (project no 82300161); Beijing High Innovation Program Spring Bud Project (project no 2-1-008-0262); Xuanwu Hospital Talent Convergence Program (project no HZ2025ZCYX003); Beijing Future Talent Training Program in Medical-Engineering Field (project no MBRC0012025063); Beijing High-level Overseas Returnee Talent Funding Project (project no 2-2-008-0243), Capital Medical University Science and Innovation Elite Plan Project (project no 2024KCJY0405), the “ National Natural Science Foundation of Youth Cultivation Project “ of “ Xuanwu Hospital, Capital Medical University, Beijing, China “ (project no QNPY2022014), the “ Person of Outstanding Ability Training Program “ of “ Xuanwu Hospital, Capital Medical University, Beijing, China “ (project no YC20220127). All authors provided critical feedback during manuscript preparation and approved the final version for publication.
Footnotes
Edited by: Vasiliki Pappa, University General Hospital Attikon, Greece
Reviewed by: Meltem Kurt Yuksel, Ankara University, Turkey
Shuhei Kurosawa, Tokyo Metropolitan Komagome Hospital, Japan
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.
Author contributions
ST: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. MS: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. YG: Conceptualization, Data curation, Methodology, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing. LS: Conceptualization, Investigation, Project administration, Supervision, Validation, Visualization, Writing – review & editing. HW: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Supervision, Validation, Writing – review & editing. QM: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Validation, Visualization, Writing – review & editing. WH: Investigation, Methodology, Supervision, Validation, Writing – review & editing. JN: Conceptualization, Data curation, Funding acquisition, Resources, Validation, Visualization, Writing – review & editing. ZC: Data curation, Investigation, Methodology, Supervision, Writing – review & editing. HH: Conceptualization, Investigation, Resources, Validation, Visualization, Writing – review & editing. YfC: Conceptualization, Project administration, Resources, Supervision, Validation, Writing – review & editing. YxL: Data curation, Formal analysis, Investigation, Software, Supervision, Validation, Writing – review & editing. YmL: Conceptualization, Resources, Software, Supervision, Validation, Writing – review & editing. YcC: Data curation, Investigation, Methodology, Validation, Visualization, Writing – review & editing. JS: Conceptualization, Formal analysis, Methodology, Validation, Visualization, Writing – review & editing. WS: Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, Writing – review & editing.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2026.1766549/full#supplementary-material
References
- 1. Young NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology Am Soc Hematol Educ Program. (2013) 2013:76–81. doi: 10.1182/asheducation-2013.1.76 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Young NS. Aplastic anemia. N Engl J Med. (2018) 379:1643–56. doi: 10.1056/nejmra1413485 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Vaht K, Göransson M, Carlson K, Isaksson C, Lenhoff S, Sandstedt A, et al. Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000-2011. Haematologica. (2017) 102:1683–90. doi: 10.3324/haematol.2017.169862 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. (2011) 365:430–8. doi: 10.1056/nejmoa1103975 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Scheinberg P. Novel therapeutic choices in immune aplastic anemia. F1000Research. (2020) 9:F1000 Faculty Rev–1118. doi: 10.12688/f1000research.22214.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. (2017) 376:1540–50. doi: 10.1056/nejmoa1613878 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. (2014) 123:1818–25. doi: 10.1182/blood-2013-10-534743 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med. (2022) 386:11–23. doi: 10.1056/nejmoa2109965 [DOI] [PubMed] [Google Scholar]
- 9. Assi R, Garcia-Manero G, Ravandi F, Borthakur G, Daver NG, Jabbour E, et al. Addition of eltrombopag to immunosuppressive therapy in patients with newly diagnosed aplastic anemia. Cancer. (2018) 124:4192–201. doi: 10.1002/cncr.31658 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Jin Y, Li R, Lin S, Jia J, Yang Y, Zhang D, et al. A real-word experience of eltrombopag plus rabbit antithymocyte immunoglobulin-based IST in Chinese patients with severe aplastic anemia. Ann Hematol. (2022) 101:2413–9. doi: 10.1007/s00277-022-04966-w [DOI] [PubMed] [Google Scholar]
- 11. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. (2021) 372:n71. doi: 10.31222/osf.io/v7gm2_v1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Fang M, Song H, Zhang J, Li S, Shen D, Tang Y. Efficacy and safety of immunosuppressive therapy with or without eltrombopag in pediatric patients with acquired aplastic anemia: a Chinese retrospective study. Pediatr Hematol Oncol. (2021) 38:633–46. doi: 10.1080/08880018.2021.1895924 [DOI] [PubMed] [Google Scholar]
- 13. Fang M. Effects of eltrombopag combined with intensive immunosuppression in treatment of patients with aplastic anemia. Med J Chin Peoples Health. (2023) 35:28–30. [Google Scholar]
- 14. Groarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, Lotter J, Baldoni D, et al. Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia. Br J Haematol. (2021) 192:605–14. doi: 10.1111/bjh.17232 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Hu XR. Eltrombopag added to standard immunosuppressive therapy in Chinese patients with very severe or severe aplastic anemia: efficacy, safety, and prognostic assessment. (master's thesis). Beijing: Chinese Academy of Medical Sciences & Peking Union Medical College; (2023). doi: 10.27648/d.cnki.gzxhu.2022.000193 [DOI] [Google Scholar]
- 16. Jie M, Fu L, Li S, He Y, Yao J, Cheng X, et al. Efficacy and safety of eltrombopag in the first-line therapy of severe aplastic anemia in children. Pediatr Hematol Oncol. (2021) 38:647–57. doi: 10.1080/08880018.2021.1900475 [DOI] [PubMed] [Google Scholar]
- 17. Lin Y, Zhang R, Lin Z, Chen Q, Chen R. Effect of eltrombopag on response to immunosuppressive therapy in patients with transfusion-dependent non-severe aplastic anemia. J Exp Hematol. (2023) 31:823–9. [DOI] [PubMed] [Google Scholar]
- 18. Yang X, Yang X, Xu C, Yan B. Effects of eltrombopag combined with cyclosporine A on serum thrombopoietin, granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor in patients with aplastic anemia. World Clin Drug. (2021) 42:1108–12. [Google Scholar]
- 19. Goronkova O, Novichkova G, Salimova T, Kalinina I, Baidildina D, Petrova U, et al. Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia. Blood Adv. (2023) 7:953–62. doi: 10.1182/bloodadvances.2021006716 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Lesmana H, Jacobs T, Boals M, Gray N, Lewis S, Ding J, et al. Eltrombopag in children with severe aplastic anemia. Pediatr Blood Cancer. (2021) 68:e29066. doi: 10.1002/pbc.29066 [DOI] [PubMed] [Google Scholar]
- 21. Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. (2003) 289:1130–5. doi: 10.1001/jama.289.9.1130 [DOI] [PubMed] [Google Scholar]
- 22. Kojima S, Hibi S, Kosaka Y, Yamamoto M, Tsuchida M, Mugishima H, et al. Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood. (2000) 96:2049–54. doi: 10.1182/blood.v96.6.2049 [DOI] [PubMed] [Google Scholar]
- 23. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. (2009) 144:206–16. doi: 10.1111/j.1365-2141.2008.07450.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Cabannes-Hamy A, Boissel N, Peffault De Latour R, Lengliné E, Leblanc T, de Fontbrune FS, et al. The effect of age in patients with acquired aplastic anaemia treated with immunosuppressive therapy: comparison of adolescents and young adults with children and older adults. Br J Haematol. (2018) 183:766–74. doi: 10.1111/bjh.15650 [DOI] [PubMed] [Google Scholar]
- 25. Zaimoku Y, Patel BA, Shalhoub R, Groarke EM, Feng X, Wu CO, et al. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. (2021) 107:126–33. doi: 10.3324/haematol.2021.278413 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Chang MH, Kim KH, Kim HS, Jun HJ, Kim DH, Jang JH, et al. Predictors of response to immunosuppressive therapy with antithymocyte globulin and cyclosporine and prognostic factors for survival in patients with severe aplastic anemia. Eur J Haematol. (2010) 84:154–9. doi: 10.1111/j.1600-0609.2009.01378.x [DOI] [PubMed] [Google Scholar]
- 27. Shinn LT, Benitez LL, Perissinotti AJ, Reid JH, Buhlinger KM, van Deventer H, et al. Multicenter evaluation of the addition of eltrombopag to immunosuppressive therapy for adults with severe aplastic anemia. Int J Hematol. (2023) 118:682–9. doi: 10.1007/s12185-023-03670-3 [DOI] [PubMed] [Google Scholar]
- 28. Patel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. (2022) 139:34–43. doi: 10.1182/blood.2021012130 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Durrani J, Groarke EM. Clonality in immune aplastic anemia: mechanisms of immune escape or Malignant transformation. Semin Hematol. (2022) 59:137–42. doi: 10.1053/j.seminhematol.2022.08.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Groarke EM, Patel BA, Shalhoub R, Gutierrez-Rodrigues F, Desai P, Leuva H, et al. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia. Leukemia. (2022) 36:2328–37. doi: 10.1038/s41375-022-01636-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Young DJ, Fan X, Groarke EM, Patel B, Desmond R, Winkler T, et al. Long-term eltrombopag for bone marrow failure depletes iron. Am J Hematol. (2022) 97:791–801. doi: 10.1182/blood-2020-141375 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Cai J. Efficacy analysis of eltrombopag combined with cyclosporine in the treatment of aplastic anaemia. J North Pharm. (2021) 18:66–7. [Google Scholar]
- 33. Chai XX, Li RX, Du XP, He Y, Liu XQ, Cheng L, et al. Eltrombopag combing with intensive immunosuppressive therapy for elderly severe aplastic anemia: clinical analysis of 35 cases. Chin J Pract Intern Med. (2021) 41:301–5. [Google Scholar]
- 34. Liang L, Li B, Cheng M. Effect of eltrombopag on clinical efficacy and safety in patients with chronic aplastic anaemia. Shenzhen J Integr Tradit Chin West Med. (2023) 33:81–3. [Google Scholar]
- 35. Martynova A, Chiu V, Mert M, Hermel D, Weitz IC. Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series. Ann Hematol. (2021) 100:933–9. doi: 10.1007/s00277-021-04401-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Zhang Y, Liu M, Zhan X. The efficacy of immunosuppression combined with Eltrombopag in the treatment of severe aplastic anemia in children. Available online at: http://qikan.cqvip.com/Qikan/Article/Detail?id=7106916895&from=Qikan_Search_Index (Accessed July 15, 2026).
- 37. Zhao Y, Yang W, Zhao X, Hu X, Hu J, Liu X, et al. Efficacy of eltrombopag with immunosuppressive therapy for children with acquired aplastic anemia. Front Pediatr. (2023) 10:1095143. doi: 10.3389/fped.2022.1095143 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.